Cardiovascular disease (CVD) is a major public health concern in most human populations. While much research effort has been directed towards identifying the genetic and environmental factors that influence an individual's risk of CVD, the potential involvement of infectious agents in disease etiology has received comparatively little attention, despite substantial evidence that infections contribute to inflammation and elevate the risk of CVD-related morbidity and mortality. We propose to assess the role of genetic factors of the human host in regulating susceptibility to infection in a systematic manner by means of a large-scale family study. In preliminary work, we have shown that serological phenotypes indicative of infection with several common bacterial and viral pathogens are heritable. Furthermore, we have mapped a locus involved in regulating susceptibility to infection by Chlamydia pneumonias by genome-wide linkage analysis in Mexican American families. In this project, we will expand our research to encompass 7 common pathogens---Chlamydia pneumoniae, Helicobacter pylori, Porphyromonas gingivalis, cytomegalovirus, hepatitis A virus, herpes simplex virus 1, and human herpesvirus 8---in a much larger pedigree sample of 2,500 Mexican Americans from San Antonio, TX. The 4 main goals of the project are to: 1) determine the phenotypic and genetic correlation of infection and inflammation;2) assess the importance of host genes in regulating susceptibility to infection;3) localize major genes involved in regulation of infection susceptibility in the human genome;and 4) identify the gene(s) and most likely functional variant(s) responsible for 2 significant linkage signals. This project takes advantage of 3 well-established family studies---the San Antonio Family Heart Study, the San Antonio Family Diabetes/Gallbladder Study, and the Veterans Administration Genetic Epidemiology Study. Genome-wide marker genotypes already exist in all 3 studies. In addition, a variety of CVD-related phenotypes, including inflammation markers, have already been measured. Serum and plasma samples from these studies are available for use in the proposed research. Relevance to Public Health: The proposed research is highly relevant to public health, given the potentially serious complications of infections with these pathogens and their likely contribution to CVD, which is a major contributor to morbidity and mortality in the US. Improved understanding of the genetic aspects of infection and its relationship with CVD risk may lead to novel strategies for prevention and treatment of infection and CVD.